Periodic Reporting for period 1 - M-Lysosomes (Identification of a novel function of lysosomes in mitosis for cancer therapy)
Periodo di rendicontazione: 2019-01-01 al 2020-12-31
Focus on mitosis is a long-standing strategy in cancer research to prevent the uncontrolled proliferation of malignant cells. Cancer cells have the capacity to highjack cellular pathways and bypass surveillance processes to survive. A common feature of cancer cells is their ability to tolerate high rate of errors during mitosis, also known as chromosomal instability (CIN). CIN is triggered by chromosome missegregation and induces chromosomal imbalance which was shown to cause intratumoral heterogeneity and the development of drug resistance in cancer cells. To prevent CIN, mitosis has to be timely and tightly regulated. The principal actor implicated in the degradation of mitotic factors is the ubiquitin-proteasome system (UPS) that leads to a rapid and sequential elimination of regulatory proteins. Interestingly, the involvement of the other cellular degradative system, aka the lysosomes, in regulating mitotic progression remains a controversial topic. The action “Identification of a novel function of lysosomes in mitosis for cancer therapy — M-Lysosomes” aimed to investigate whether lysosome-dependent degradation plays an active role during mitotic progression to identify a new therapeutic window for cancer treatment.
Cancer is a burden in almost every family and is the second leading cause of death worldwide based on the World Health Organization. The impact of cancer on society ranges from emotional, economical and physical distresses. Even though incredible scientific and medical advances have revolutionized cancer treatments in the last decades, cancer remains a large and complex group of diseases with limited therapies. By interconnecting two prominent fields in cancer research, autophagy/lysosomes and cell division, the findings emerging from this Marie Skłodowska-Curie Action (MSCA) offer promising outcomes for cancer treatment with direct impact on both the scientific community and the society.
The objectives of this project have been to (1) investigate whether lysosomes are involved in mitotic progression and (2) analyze the repercussion of dysfunctional lysosomes on chromosomal instability. This original and innovative scientific project demonstrated a protective function of lysosomes specifically during mitosis to prevent CIN. Our findings revealed an additional layer of complexity in the regulation of mitosis and opened new opportunities to design combination treatment for cancer patients. In addition, this MSCA Individual Fellowship aimed to foster the development of my professional career as an independent researcher.
Cancer is a burden in almost every family and is the second leading cause of death worldwide based on the World Health Organization. The impact of cancer on society ranges from emotional, economical and physical distresses. Even though incredible scientific and medical advances have revolutionized cancer treatments in the last decades, cancer remains a large and complex group of diseases with limited therapies. By interconnecting two prominent fields in cancer research, autophagy/lysosomes and cell division, the findings emerging from this Marie Skłodowska-Curie Action (MSCA) offer promising outcomes for cancer treatment with direct impact on both the scientific community and the society.
The objectives of this project have been to (1) investigate whether lysosomes are involved in mitotic progression and (2) analyze the repercussion of dysfunctional lysosomes on chromosomal instability. This original and innovative scientific project demonstrated a protective function of lysosomes specifically during mitosis to prevent CIN. Our findings revealed an additional layer of complexity in the regulation of mitosis and opened new opportunities to design combination treatment for cancer patients. In addition, this MSCA Individual Fellowship aimed to foster the development of my professional career as an independent researcher.
Work was conducted via 4 research objectives (RO). RO1 aimed to assess the contribution of lysosomes acidification capacity and localization to induce the formation of the toroidal nucleus. The characterization of the role of lysosomes in mitosis was elaborated in RO2. The identification of lysosomal substrates in mitosis by proteomic analysis was developed in RO3. Finally, the objective of RO4 was to determine the relevance of the formation of toroidal nuclei in cell fate and its importance on malignant transformation.
I completed my project successfully, even under the extraordinary situation experienced in COVID-19 pandemic. The results demonstrated that lysosomes and autophagic vesicles are present and active during cell division and that lysosome acidification capacity and trafficking are important to maintain correct mitotic progression. We demonstrated that impairment of lysosomes induced mitotic errors, which correlated with an increase of the formation of the toroidal nucleus. These findings led us to propose to use the toroidal nucleus as a novel biomarker for chromosomal instability. Although lysosome disruption clearly induced the formation of toroidal nuclei, we corroborated that defects in chromosome segregation is the leading cause for the formation of the toroidal nuclei. We further investigated the presence of autophagic vesicles during mitotic progression and found that functional autophagy is involved in the maintenance of mitosis fidelity. We identified more than 150 novel lysosome substrates specifically during mitosis by proteomic analysis. We further investigated two proteins associated with the cohesin complex that are directly involved in chromosomal segregation. I am last and corresponding author of the peer-reviewed article in one of the top journals in the field (published in 2020, IF: 10.79). Even affected by COVID-19 pandemic, I presented our findings in 6 renowned scientific conferences during the duration of my MSCA Individual Fellowship. My participation to international conferences increased my professional network and I established a fruitful collaboration with Dr Charles Day (Hormel Institute-Mayo Clinic, USA). Following the publication of our manuscript, I was invited as guest editor by two journals “Cells” and “Frontiers in Cell and Developmental Biology” to spearhead the development of special issues on the topic (for 2021). With the support of my MSCA and of companies specialized in science communication, I created 2 videos to broadcast my research project and to highlight our findings (one was launched in 2019 and has more than 1000 views on YouTube, the other was uploaded recently and already reached more than 100 views). I developed educational material to discuss cell biology in primary schools as a Marie Skłodowska-Curie ambassador (only in 2019 due to COVID-19 pandemic). To fulfil my interest in developing my own research laboratory, I participated to internal training at IDIBELL and in February 2020 to a 3-days course focused on laboratory leadership organized by EMBO.
I completed my project successfully, even under the extraordinary situation experienced in COVID-19 pandemic. The results demonstrated that lysosomes and autophagic vesicles are present and active during cell division and that lysosome acidification capacity and trafficking are important to maintain correct mitotic progression. We demonstrated that impairment of lysosomes induced mitotic errors, which correlated with an increase of the formation of the toroidal nucleus. These findings led us to propose to use the toroidal nucleus as a novel biomarker for chromosomal instability. Although lysosome disruption clearly induced the formation of toroidal nuclei, we corroborated that defects in chromosome segregation is the leading cause for the formation of the toroidal nuclei. We further investigated the presence of autophagic vesicles during mitotic progression and found that functional autophagy is involved in the maintenance of mitosis fidelity. We identified more than 150 novel lysosome substrates specifically during mitosis by proteomic analysis. We further investigated two proteins associated with the cohesin complex that are directly involved in chromosomal segregation. I am last and corresponding author of the peer-reviewed article in one of the top journals in the field (published in 2020, IF: 10.79). Even affected by COVID-19 pandemic, I presented our findings in 6 renowned scientific conferences during the duration of my MSCA Individual Fellowship. My participation to international conferences increased my professional network and I established a fruitful collaboration with Dr Charles Day (Hormel Institute-Mayo Clinic, USA). Following the publication of our manuscript, I was invited as guest editor by two journals “Cells” and “Frontiers in Cell and Developmental Biology” to spearhead the development of special issues on the topic (for 2021). With the support of my MSCA and of companies specialized in science communication, I created 2 videos to broadcast my research project and to highlight our findings (one was launched in 2019 and has more than 1000 views on YouTube, the other was uploaded recently and already reached more than 100 views). I developed educational material to discuss cell biology in primary schools as a Marie Skłodowska-Curie ambassador (only in 2019 due to COVID-19 pandemic). To fulfil my interest in developing my own research laboratory, I participated to internal training at IDIBELL and in February 2020 to a 3-days course focused on laboratory leadership organized by EMBO.
The development of this project went beyond its initial objectives, with the demonstration of two great scientific advances. The characterization of the toroidal nucleus as a novel biomarker for chromosomal instability will have tremendous consequences especially in cancer research as we detected toroidal nuclei in 80% of the tested cancer cell lines. Until now, scientists referred to chromosomal instability by analysing the presence of the micronuclei. Complementary analysis implementing the detection of toroidal nuclei will enhance our capability to expose chromosomal anomalies. The function of lysosomes in cell biology was restricted to its cytosolic localization in non-mitotic cells. Our findings highlight the importance of lysosome-dependent degradation for the accurate progression of the mitosis and, thus for the preservation of genomic stability. Therapeutic strategies based on the modulation of autophagy and lysosomes in mitotic cells will favour the development of novel treatment for cancer patients. Regarding my professional advances, this MSCA fortified my skills in management and reinforced my maturity to lead and manage a research project. My MSCA research project is the foundation of the investigation I plan to further explore and led to my consolidation as a recognized expert in the field of autophagy, which will greatly impact my career as independent researcher.